Abstract
Hepatitis C virus (HCV) core protein features many intriguing properties and plays a pivotal role in cellular immunity, cell growth, apoptosis, cell transformation, and eventually in tumor development. However, the role of B cells, the primary players in the humoral immune response, during HCV infection is largely unknown. To explore the molecular effects of HCV core on human B cells, we conducted gene expression profiling of serial RNA samples from B cells that were infected with adenovirus harboring full-length HCV core protein and beta-galactosidase as a reference using a microarray platform containing 22,149 human oligo probes. The entire experiment was performed in duplicate in B lymphocytes that were isolated from two individual donors and incubated for up to 3 days after infection with adenovirus expressing HCV core protein to identify dynamic gene expression patterns. Differential expression of representative genes was validated by quantitative RT-PCR. We found that HCV core significantly inhibited B-lymphocyte apoptosis. We showed a dramatic downregulation of MHC class II molecules in B cells expressing HCV core, whereas the expression of immunoglobulin genes was not significantly altered. Moreover, genes associated with leukemia and B-lymphoma were consistently upregulated by HCV core. In contrast, downregulation of caspase-1 and caspase-4 was found to be associated with core's ability to prevent B-lymphocyte apoptosis. In summary, we have identified several clusters of genes that are differentially expressed in human B lymphocytes expressing HCV core, suggesting a potential impairment of antigen processing and presentation, which may provide more insights into HCV infection in B lymphocytes.
Highlights
Hepatitis C virus (HCV), with 1.8%prevalence of infection in the United States and 170 million worldwide [1], is a major cause of cirrhosis and potentially leads to hepatocellular carcinoma (HCC)
A number of microarray analyses have been performed in chimpanzees and in patients infected with HCV virus in an attempt to identify specific gene expression profiling and potential markers [10,19]
The role of HCV, and in particular HCV core protein, in regulation of gene expression in human primary B cells has not been studied by microarray analysis
Summary
Hepatitis C virus (HCV), with 1.8%prevalence of infection in the United States and 170 million worldwide [1], is a major cause of cirrhosis and potentially leads to hepatocellular carcinoma (HCC). HCV replicates in T lymphocytes and suppresses T-cell proliferation and cytokine production [3]. In patients with chronic HCV infection, the frequencies of antiviral CTLs are relatively low [4], and the proliferative response of HCVspecific CD8+ T cells is impaired [5]. The production of Th1-type cytokines (i.e., IL-2 and IFN-γ) is dramatically suppressed in peripheral T cells of chronic HCV patients [6,7]. These observations suggest that HCV chronic infection may be the result, at least in part, of an inability to mount effective T-lymphocyte responses, indicating that HCV gene products might be in-
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